Metabolism and pharmacokinetics of novel oral prodrugs of 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) in dogs.
OBJECTIVE
A series of prodrugs designed to enhance the oral bioavailability of the antiretroviral agent 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA; 1) have been synthesized, including a bis-(acyloxymethyl) ester 2 and a series of bis-(alkoxycarbonyloxymethyl) esters 3-9. The in vitro biological stability and in vivo pharmacokinetics of these prodrugs were evaluated to support selection of a prodrug candidate for clinical evaluation.


METHODS
The in vitro biological stability of the prodrugs was examined in dog tissues (intestinal homogenate, plasma and liver homogenate). The apparent half-lives were determined based on the disappearance of prodrug using reverse-phase HPLC with UV detection. Oral bioavailability of PMPA from each prodrug was determined in fasted beagle dogs. Concentrations of PMPA in plasma were determined by HPLC following fluorescence derivatization. Data for prodrugs were compared to historical data for intravenous PMPA.


RESULTS
All prodrug were rapidly hydrolyzed in dog plasma and tissues (t1/2 < 60 min). In fasted beagle dogs, bis-[(pivaloyloxy)methyl] PMPA (bis-POM PMPA) 2 had the highest oral bioavailability as PMPA (37.8 +/- 5.1%). The oral bioavailabilities of PMPA from bis-(alkoxycarbonyloxymethyl) esters ranged from 16.0% to 30.7% and PMPA was the major metabolite formed.


CONCLUSIONS
There was a correlation between oral bioavailability and intestinal stability of bis-(alkoxycarbonyloxymethyl) ester prodrugs (r2 = 0.96). Lipophilicity (log P) was not a good predictor of oral bioavailability. The most labile prodrugs in dog intestinal homogenates, bis-(n-butyloxycarbonyloxymethyl) PMPA 5 and bis-(neo-pentyloxy-carbonyloxymethyl) PMPA 8 (t1/2 < 5 min) had the lowest oral bioavailabilities. Based on good oral bioavailability (30.1%), chemical and intestinal stability bis-(isopropyloxycarbonyloxymethyl) PMPA (bis-POC PMPA) 4 was selected as a candidate for clinical evaluation.
Shaw
J P
JP
Gilead Sciences, Inc., Foster City, California 94404, USA.
Sueoko
C M
CM
Oliyai
R
R
Lee
W A
WA
Arimilli
M N
MN
Kim
C U
CU
Cundy
K C
KC
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D004285:Dogs; D004355:Drug Stability; D004950:Esterases / Q000378:metabolism; D006207:Half-Life; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D000068698:Tenofovir
D019380:Anti-HIV Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; D000068698:Tenofovir; D004950:Esterases; D000225:Adenine